Process for the preparation of a pharmaceutical composition containing pirfenidone in sustained-release tablet form and its application in the regression of human chronic renal failure, breast capsular contracture and hepatic fibrosis

ABSTRACT

The instant invention relates to a process for the preparation of a pharmaceutical composition in sustained-release tablet form comprising from 600 milligrams to 2400 milligrams of Pirfenidone (PFD), in such a way that the drug is bioavailable during an extended period of time of 12 hours from its administration. In this way, the anti-fibrotic and anti-inflammatory action of the drug Pirfenidone is optimized. Moreover, the instant invention offers advantages and a higher therapeutic efficacy compared to other pharmaceutical forms of Pirfenidone for oral administration and its therapeutic application in the regression of chronic renal failure secondary to primary glomerulosclerosis; it shows a better activity with regard to the reduction and/or regression of deleterious effects in breast capsular contracture observed after the surgical implantation of breast implants in humans and has an important anti-TNF-α and anti-TGF-β1 action for the treatment of hepatic fibrosis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority under 35 U.S.C. § 120 to U.S. patent application U.S. Ser. No. 15/831,650, filed Dec. 5, 2017, which is a divisional of and claims priority under 35 U.S.C. § 120 to U.S. patent application U.S. Ser. No. 15/177,760, filed Jun. 9, 2016, which is a divisional of and claims priority under 35 U.S.C. § 120 to U.S. patent application U.S. Ser. No. 14/233,600, filed May 20, 2014, now issued as U.S. Pat. No. 9,408,836, which is a national stage filing under 35 U.S.C. § 371 of international PCT application, PCT/MX2012/000067, filed Jul. 13, 2012, which claims priority under 35 U.S.C. § 119(a) to Mexican Application, MX/a/2011/007675, filed Jul. 19, 2011, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of a pharmaceutical composition containing pirfenidone (PFD) in sustained-release tablet form, offering advantages and a better therapeutic efficacy compared to other oral pharmaceutical forms of pirfenidone and its therapeutic application in the regression of human chronic renal failure, breast capsular contracture and hepatic fibrosis.

BACKGROUND OF THE INVENTION

Pirfenidone is a drug constituted by a small molecule, the chemical name of which is 5-methyl-1-phenyl-2-(1H)-pyridone. It is a non-peptidic synthetic molecule with a molecular weight of 185.23 Dalton. Its chemical formula is C₁₂H₁₁NO, and its structure is known. Currently, pirfenidone is under clinical evaluation as a wide spectrum anti-fibrotic drug. Pirfenidone has anti-fibrotic and anti-inflammatory properties that are reflected in its activity of lowering the expression of TGF-1, INF-ex, PDGF and most importantly, the expression of different types of collagens. Currently, Phase III studies are being conducted on humans with regard to lung fibrosis, chronic renal failure secondary to kidney glomerulosclerosis, hepatic cirrhosis and breast capsular contracture.

Basic and clinical research works, already published or in process of being published, have shown that pirfenidone lowers the progressive advance of fibrosis lesions. Most importantly, pirfenidone performs said actions in a safe and non-toxic manner. Moreover, it is known that pirfenidone prevents the formation of fibrotic lesions after damage to a given organ, for example liver, skin, kidney, etc.

It is known that one of the mechanisms through which pirfenidone performs its therapeutic effects is through the modulation of the action of several cytokines. Pirfenidone is a potent inhibitor of fibrogenic cytokines and INF-ex. It is well documented that pirfenidone inhibits the excessive biosynthesis and release of several fibrogenic cytokines such as IGF-1, bFGF, PDGF, and EGF. Zhang S. et al., Australian and New England J. Ophtalmology 26:S74-S76 (1998). Other scientific reports also show that pirfenidone blocks the synthesis and liberation of excessive quantities of INF-ex from macrophages and other cells, Cain et al., Int'l J Immunopharmacology 20:685-695 (1998).

On the other hand, pirfenidone is a drug that has been applied for restoring tissues with fibrotic lesions and preventing fibrotic lesions as well. This compound, per se, is a known compound and its pharmacological effects have been described, for example, in Japanese applications KOKAI Numbers 87677/1974 and 1284338/1976, as an anti-inflammatory agent that includes anti-pyretic and analgesic effects. U.S. Pat. No. 3,839,346, published on Oct. 1, 1974; U.S. Pat. No. 3,974,281, published on Aug. 10, 1976; U.S. Pat. No. 4,042,699, published on Aug. 16, 1977, and U.S. Pat. No. 4,052,509, published on Oct. 4, 1977, describe methods for obtaining pirfenidone, as well as its use as anti-inflammatory agent. The anti-fibrotic activity of 5-methyl-1-phenyl-2-(1H)-pyridone is described in Mexican patent 182,266.

New applications of pirfenidone have been discovered that are the object of the instant invention, showing that the compound is active in the reduction of the deleterious effects (breast capsular contracture) observed after the surgical implantation of breast implants in humans.

Moreover, as described and illustrated in the instant invention, pirfenidone is also effective in the regression of chronic renal failure secondary to primary human glomerulosclerosis and hepatic fibrosis.

Modern life is characterized by a cult of vanity and self-esteem both for men and women. For this reason, aesthetic surgery is in high demand nowadays. One of the most requested embodiments in aesthetic surgery is breast implant. Although this type of surgery is every day safer, the presence of side or adverse effects is still common. The deleterious effects observed after the placement of the breast implants are inflammation, capsular contracture and fibrosis development. Several materials have been tested for reducing said side effects.

The current beauty concepts have increased the demand for breast surgery for reconstructive and beauty purposes. However, despite the great usefulness of said medical procedure, one of the most frequent complications of post-surgery is the swelling and contracture of the capsule around the implant. Said complications cause malformation, hardness and breast pain deriving in patient's physical and psychological alterations. The causes and histopathogenesis of capsular contracture are not clearly understood. Various publications mention a variable incidence ranging from 0 to 74% (1), depending on the implantation, the type of implant cover, the surface texture and the anatomic site (2) (subglandular or subpectoral). The causes of these complications can be liquid accumulation in the tissue of the implants bag, intense inflammatory response, sub-clinical infection, age of the patient, foreign materials and the alteration of cellular and molecular mechanisms in the implantation area. When an implant is placed, the body reacts encapsulating it and starting a rejection reaction (3.4) with the formation of a hypertrophic scar (5.6). This immune response produces cytokines and growth factors such as IL-1, IL-6, TNF-α, PDGF and TGF-β1 (7, 8). The presence of myofibroblasts in the capsule structure with alpha-SMA (alpha-smooth muscle actin) production has been reported, wherein the most deformed capsules show the highest alpha-SMA production, suggesting that activated myofibroblasts play a direct part in contracture development (8). It has also been shown that the number of fibroblasts present in the tissue is proportional to contracture thickness (9). In order to reduce fibroblasts activation and wound contracture, steroid infiltration in the wound and in the inner part of the implant has been used with minor complications. Said complications are thin skin, fine tissue atrophy, stratification, blue-skin and implant exposition. However, the side effects of steroids and other drugs used are fairly important and their continuous and prolonged use should be avoided.

Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) (PFD) has shown to be efficacious in the prevention of fibrosis formation both in vitro as well as in vivo. It inhibits lung fibrosis (10), peritoneal adherence (11), liver cirrhosis (12, 13), uterine fibromyoma (14), kidney fibrosis (15), keloid scars (16) and delays the development of central nervous system tumors. Pirfenidone can also highly specifically inhibit cytokines such as TNF-alpha, FGF, PGDF and TGF-beta in the human fibroblast blocking the G1 phase of the cellular cycle. Because breast implant induces fibrosis and inflammation and because pirfenidone has shown anti-fibrotic and anti-inflammatory characteristics, the instant invention evidences the effect of pirfenidone in the inhibition of the capsular contracture in breast implant in humans.

Tumor Necrosis Factor-Alpha (TNF-α)

-   -   The TNF protein family includes TNF-α, TNF-β, Fas ligand, CD40         ligand, OX-40, RANK-L (receptor activator of nuclear factor         kappa-B ligand) and TRAIL (TNF-related apoptosis inducing         ligand).     -   For historical reasons it is denominated TNF-α for         distinguishing it from TNF-β or lymphotoxin.     -   Originally it was identified as a substance present in the serum         of animals treated with bacterial endotoxin (lipopolysaccharide         or LPS) causing in vivo tumor necrosis (its name is derived from         this).     -   The main TNF cellular source is activated mononuclear phagocytes         although antigen stimulated T lymphocytes, NK lymphocytes and         mastocytes can also secrete it.     -   TNF is the main mediator of the acute inflammatory response to         gram negative bacteria and other infectious microorganisms.     -   Its main biological action is to stimulate the attraction of         neutrophils and monocytes to the infection zones and to activate         said cells for microorganism eradication.     -   Mononuclear phagocytes come in two forms: anchored to membrane,         and soluble.     -   The TNF anchored to membrane form is separated by a membrane         associated metalloprotease (MMP-MT) and is released. Three of         these polypeptides unite and a TNF circulating protein is         formed.     -   There are two TNF receptors (TNF-RI and TNF-RII).     -   Type I receptor can stimulate the gene expression of         inflammatory mediators or induce apoptosis.     -   The pro-inflammatory or anti-apoptotic route is initiated by the         union of TRADD (TNF Receptor-Associated Death Domain) to the         intracytoplasmatic domain of the TNF receptor followed by TRAF-2         (TNF Receptor-Associated Factors) or RIP-1 (Receptor Interacting         Protein), leading to NF-kB and Ap-1 dependent gene expression.     -   However, if instead of binding to TRAF or RIP it binds to FADD         (FAS-Associated Death Domain), this causes apoptosis because it         cuts pro-Caspase 8 and said pro-Caspase 8 in turn activates         caspase effectors such as Caspase 3, this being the apoptotic         route.     -   If type II receptor binds directly to TRAF, it causes gene         expression of inflammatory mediators.     -   The genes induced by TNF receptors code mainly for inflammation         mediators and anti-apoptotic proteins.     -   Based on the above, use of TNF-α receptor blockers is one of the         strategies designed to obliterate inflammatory response.

Thus, in the instant invention it is described and shown that pirfenidone has an extremely potent and selective TNF-α inhibiting action. This information is shown in FIG. 6.

Transforming Growth Factor Beta (TGF-β)

-   -   TGF-β was isolated from human platelets in the 1980's and was         identified as a product of cells transformed by the murine         sarcoma virus. It was later named transforming growth factor         beta for its capacity to cause a phenotypic transformation in an         epithelial cells culture because it induced reversible         fibroblasts transformation.     -   TGF-β main action in the immune system is to inhibit lymphocytes         proliferation and activation.     -   Outside the immune system, TGF-β is considered the main trigger         for the production of extracellular matrix components, inducing         fibrosis through the stimulation of the production of collagen         type I, III and IV, fibronectin, laminin and proteoglycans. It         is increased in hepatic, lung and renal fibrosis both in         experimental models as well as in humans.     -   It is synthesized as an inactive dimeric precursor.     -   Active TGF-β binds to the extracellular domain of type II         receptor. Ligand binding promotes TβRII intracytoplasmatic         autophosphorylation because of its serine/threonine kinase         activity, and in turn TβRII phosphorylates type I receptor,         triggering thus Smads (signal transducing intracellular         molecules) activation, able to translocate to the nucleus and         regulate transcription of target genes such as Smad 7, PAI-I         collagen I, PDGF an TGF-3 itself.     -   Smad2/3-Smad4 complexes in the nucleus can associate with         transcription co-activators and co-repressors.     -   Three co-repressors are identified for Smad: TGIF protein and         two related proteins denominated SnoN and c-Ski. All of them are         important repressors of the TGF-β signaling route, although         their function in hepatic fibrosis is not fully described.

Thus in the instant invention it is described and shown that pirfenidone has an extremely potent and selective inhibiting action against TGF-β production. This information is shown in FIG. 5.

OBJECTS OF THE INVENTION

One of the objects of the instant invention is to describe a process for manufacturing a pharmaceutical composition in sustained-release tablet form comprising from 600 milligrams to 2400 milligrams of pirfenidone in such a way as to make the drug bioavailable during a prolonged period of time of 12 hours from its administration. Thus, the anti-fibrotic and anti-inflammatory action of the drug pirfenidone is optimized.

A further object of the instant invention is that the administration of sustained-release tablets containing pirfenidone is effective for the regression of chronic renal failure secondary to primary glomerulosclerosis.

A further object of the instant invention is that the administration of sustained-release tablets containing pirfenidone lowers and/or reduces the deleterious effects of breast capsular contracture observed after surgical implantation of breast implants in humans.

Moreover, a further object of the instant invention is the anti-TNF-α and anti-TGF-β actions of pirfenidone in sustained-release tablets for the treatment of hepatic fibrosis.

The instant invention is illustrated but not limited by the above mentioned objects; moreover its applications as treatment methods and/or pharmaceutical uses in drug preparation together with an acceptable pharmaceutical vehicle for the treatment or regression of chronic renal failure are shown, as well as for the treatment, reduction and/or regression of the deleterious effects in breast capsular contracture and for the treatment of hepatic fibrosis.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features and advantages of the invention will be evident from the following detailed description, the objects and preferred embodiments, the attached claims and the enclosed drawings or Figures, wherein:

FIG. 1 shows a diagram of breast capsular contracture evolution during the study considering the percentage according to the Baker scale with regard to the number of cases. A comparison between the cases treated with PFD is also shown. All the cases show an important improvement after PFD administration. The six-month follow-up shows only one case of relapse.

FIG. 2 shows the photograph of a patient with bilateral Breast Capsular Contracture diagnosis. The image on the left hand side shows the right breast with a grade IV contracture and the left breast with a grade III contracture; the central picture shows the same patient after six-month PFD administration, in which the left breast shows an improvement to a Not Detectable by Ultrasound or Clinical Examination state, the right breast shows an improvement to grade III. The right panel shows the image obtained at six-month follow-up, in which the lack of relapse is evidenced.

FIG. 3 shows the photograph of a patient with a bilateral Breast Capsular Contracture diagnosis. The image on the left hand size shows a grade IV breast capsular contracture. The image of the right hand side shows the same patient at the end of the protocol with both breasts classified as Capsular Contracture Not Detectable by Ultrasound or Clinical Examination.

FIG. 4 shows a photograph of a patient with a bilateral Breast Capsular Contracture diagnosis treated with capsulectomy. The image on the left-hand side shows both breasts with grade IV contracture at the time of the evaluation before capsulectomy; the image on the right-hand side shows the same patient at the six-week evaluation after capsulectomy, where a regression of the breast contracture to grade III in the right breast and to grade II in the left breast can be observed.

FIG. 5 shows a diagram with TGF-β1 serum levels determination in female rats submitted to the placement of silicone implants in mammary glands for inducing contracture development.

FIG. 6 shows a diagram with TNF-α serum levels determination in female rats submitted to the placement of silicone implants in mammary glands for inducing contracture development.

DETAILED DESCRIPTION OF THE INVENTION

The manufacturing process steps of the tablets in general are described as following.

General Process for Manufacturing the Tablets:

Order issuance,

Equipment and area cleaning,

Supply of raw materials, Powder screening, Granulate mixing, Drying, Final mixing,

Compression, Blistering, Conditioning,

Supply of packaging material, and

PT warehouse.

Although the general tablet manufacturing process is shown above, in the instant invention the detailed process for the manufacturing of a pharmaceutical composition in sustained-release tablet form comprising 600 mg of pirfenidone is detailed, wherein said process comprises the following steps:

Step 1.

Pirfenidone and silicium dioxide are screened through a 30-mesh screen in the oscillating granulator and placed in the ribbon blender and mixed during 5 minutes.

This mixing is performed to obtain a better flow of the active principle because pirfenidone does not show good flow characteristic and silicium dioxide supplies said desired feature because of its anti-adherent properties.

Step 2.

Microcrystalline cellulose, low viscosity hydroxypropylmethylcellulose (HPMC) and high viscosity hydroxypropylmethylcellulose (HPMC) are screened through a 30-mesh screen in the oscillating granulator and placed in the ribbon blender of step 1 and mixed during 15 minutes.

The monocrystalline cellulose is a diluent giving the tablet an appropriate hardness although low compression forces are applied; moreover it contributes to the low brittleness of the tablets. The mixture of low and high viscosity HPMC forms the release matrix; it is made in a mixture ratio appropriate for the slow and steady release of the active principle till its complete release at twelve hours permitting thus a prolonged active principle bioavailability.

Step 3.

Sodium stearyl fumarate is screened through a 30-mesh screen in the oscillating granulator and placed in the ribbon blender of step 1 and mixed during 3 minutes.

Sodium stearyl fumarate is a lubricating agent that prevents the adherence of the tablets on the surface of the punches during tablet formation; moreover it reduces friction between particles.

Step 4.

The granulate obtained is formed in tablets in the stokes tablet making machine equipped with elongated punches having the following compression parameters:

Average weight: 850 mg±5%; Hardness: maximum 10 kgF; Brittleness: below 1%.

Finally, quality control sampling is performed in order to determine if the finished product meets the desired specifications.

SUSTAINED-RELEASE TABLETS Comprising 600 mg of Pirfenidone

Quantitative Formula Composition:

Compound Quantity Pirfenidone 600.0 mg Microcrystalline cellulose 118.8 mg Low viscosity HPMC 70.0 mg High viscosity HPMC 46.5 mg Silicium dioxide 8.5 mg Sodium stearyl fumarate 6.2 mg

Pirfenidone Bioavailability Study in Healthy Volunteers According to the Pharmacopoeia Standards

In this study with 11 healthy volunteers, it was shown that the bioavailability of this drug in 600 mg sustained-release tablet form is prolonged till 12 hours and blood effective therapeutic concentration was determined according to the pharmacopoeia standards. Said analyses were performed by a laboratory authorized by the Mexican Health Secretariat (Data not shown).

Maximum concentration data evidenced that the bioavailability is extrapolated to other lower concentrations, i.e., 100, 200 or 400 mg.

Application of Sustained-Release Tablets Containing Pirfenidine in the Regression of Chronic Renal Failure

Although diabetic nephropathy is the main cause of terminal renal disease after the fourth decade of life, in the young adult there are other causes that are in some way the continuity of infants and adolescent pathologies, so that the population under 40 years of age in need of functional replacement through dialysis and transplant most frequently relates to primary or secondary glomerular diseases. The first cause of terminal renal disease under 16 years of age is primary glomerular diseases many of which are diagnosed at a late stage when they have already caused severe renal structural damage, i.e., damaged over 60% of the nephron population and unfortunately manifest themselves in advanced phases of renal failure. The earliest manifestation of a primary glomerular disease is constituted by proteinuria documented, in most of the cases, as “nephrotic syndrome”, this generally progressive finding being usually followed by systemic arterial hypertension and, finally, progressive functional failure.

Several mechanisms are responsible for damage progression, one of them being intraglomerular hypertension and hyperfiltration, initiating a disorderly response that induces glomerular sclerosis and nephron destruction. The increase of intraglomerular hydrostatic pressure can cause an increase of mesangial cell contraction and a production increase of TGF-β, and various cytokines and growth factors.

They include vasoactive agents such as angiotensin II, thromboxanes, endothelin-1 and type IL-1 and TNF-α cytokines. It is currently considered that massive and persistent proteinuria per se is an independent factor contributing to the progression in all the forms of chronic renal disease. The excess of protein filtration within the proximal tubule and its subsequent endocytosis can represent a pathological mechanism in the renal fibrosis development. A possible scenario for explaining the relationship between proteinuria grade and progression to renal failure can be related to the tubular epithelial cells that, upon endocyting proteins, activate and over-express chemotactic factors such as monocytes (MIP-1), promoting the infiltration of mononuclear cells, among them macrophages that are a rich source of TGF-β promoting the phenotypic change of fibroblasts in myo-fibroblasts, increasing thus the extracellular matrix synthesis and type I and III fibrillar collagen deposits contribute to the interstitial fibrosis.

The severity of this deposit lowers thus the glomerular filtration rate.

Based on the above exposed mechanisms, strategies have been used in the past years to try to reduce said deleterious factors, such as:

Low-protein diets for reducing hyperfiltration and concomitant drugs such as Inhibitors of Angiotensin-Converting Enzyme (Enalapril, Lisinopril), or Angiotensin Receptors Antagonists II (Sartanes), that lower intraglomerular hypertension and thus considerably reduce proteinuria, mechanisms that are responsible for the damage.

Direct Background

For logical reasons, the use of an anti-fibrotic agent, especially if it lowers TGF-β and TNF-α expression, will be useful for the treatment of patients in the initial phases of glomerular nephropathy. This will detain the progressive and continuous deterioration observed in these patients and prevent early transplantation need.

In animal models, it has been shown that pirfenidone:

-   -   Can prevent the development of progressive renal disease.     -   Reduces proteinuria levels.     -   Reduces urea nitrogen and serum creatinine levels.     -   Improves renal function reducing collagen accumulation in the         renal cortex.     -   It also reduces TGF-β expression.

The animals treated with pirfenidone grew and developed normally and without toxic effects.

Pirfenidone is an anti-fibrotic agent that has shown to be effective in vitro or in vivo for the prevention and resolution of the accumulation in experimental models of:

Pulmonary fibrosis

Renal fibrosis

Hepatic fibrosis.

The use of the drug in humans has had the same objective focused onto different apparatus and systems. Two reports from 2003 and 2006 of a study conducted by Dr. Armendariz et al present the results obtained with pirfenidone in patients with hepatic fibrosis. Said study has currently been expanded to a larger population and has shown beneficial effects as evidenced through hepatic biopsy.

On the other hand, a study was conducted on renal failure patients treated with hemodialysis and having a history of sclerosing peritonitis. Drug pharmacokinetics was evaluated in said patients. The study showed that it is not necessary to adjust the pirfenidone dose in patients with renal damage and that pirfenidone is well tolerated by patients with Terminal Chronic Renal Failure (TCRF) without showing significant side effects.

Pirfenidone was also evaluated by Cho Me et al in 2007 on patients with nephrotic syndrome and focal segmental glomerulosclerosis in order to delay renal function impairment, obtaining favorable results. The Institute for Renal Digestive and Diabetes Diseases as well as the Institute of Health of the United States of America gave information regarding the use of pirfenidone in two studies authorized by the FDA, one of them on patients with focal segmental glomerulosclerosis in various stages of renal damage and the second on patients with diabetic nephropathy.

Rationale

It is important to take into account that the expensive chronic renal failure (CRF) has become a red spot in Mexico because of its growth rate (11%). Appropriate public health policies must be established in order to absorb the future costs of this unavoidable problem. The public health system offers renal replacement (dialysis) therapies to some 70,000 patients, but it is calculated that for each patient receiving attention, there are two non treated persons. Because of the lack of resources, if this growth rate continues, only one out of four patients will have access to therapy.

For this reason, in pharmacoeconomic terms, the implementation of new therapeutic strategies, such as the one described herein, has enormous relevance.

Renal damage and its progression can be studied through laboratory methods focused onto measuring proteinuria magnitude, renal function evaluated through creatinine clearance, reciprocal creatinine (1/creatinine) and cystatin C and with Doppler ultrasound comparative findings in which anatomical, echosonographic, corticomedular changes as well as flow rate in different renal areas and resistance indexes can be observed; finally, the golden rule to evaluate the magnitude of the damage is the hystological study that expresses the affected structures and the fibrosis extension. Not all these studies can be conducted routinely, because renal biopsy is an invasive procedure that can only be justified reiteratively in patients already submitted to a first procedure for results comparison purposes. On the other hand, laboratory and office methods can be conducted with a defined chronogram.

Study Design

The present study is a prospective, open label, 12-month clinical trial including 30 patients with primary nephropathy, with renal damage (stages 1 to 4 of the KDIGO Classification) between 10 and 40 years of age, from both sexes. All the patients were observed with regard to their evolution by means of laboratory examinations at least three months before their inclusion into the study. Said evaluation phase was useful so that the patient could become his/her own control.

All of the patients received oral Pirfenidone (in sustained-release tablet form) administered every 12 hours containing 2400 mg/1.73 m² BSA, equivalent to 1400 mg/m BSA/24 hrs.; besides, they also received a conventional treatment appropriate for primary nephropathy and CRF, such as antihypertensives, alpha-ketoanalogues, phosphate chelating agents, angiotensin II antagonist, low-protein diet, etc.

They were evaluated every two months during the first six months, and then at 9- and 12-month follow up with laboratory determinations including cystatin C value and creatinine clearance, reciprocal creatinine and proteinuria in 24-hour collection. Two Doppler ultrasonographic studies were performed on each patient at the beginning of the study and at 12 months. Drug adverse events were evaluated and the loss of renal function and loss percentage were quantified.

Experimental Evidence/Results

-   -   Taking into account the above, a study was conducted with a         patient population having renal damage diagnosis evidenced         through laboratory or office methods as common denominator and         wherein the use of Pirfenidone at therapeutic doses calculated         per m²/Body Surface Area was useful for delaying or modifying         renal damage.     -   Pirfenidone influenced positively renal damage progression rate         (phases 1-4 according to KDIGO classification) in patients with         chronic renal failure secondary to primary nephropathy.     -   The use of Pirfenidone in renal function was monitored through         cystatin C, plasma reciprocal creatinine and creatinine         clearance in 24-hour urine collection.     -   Moreover, the beneficial effect of Pirfenidone on proteinuria         was determined and it was evidenced, through the analysis of the         comparative ultrasonographic changes at the beginning and the         end of the treatment, that Pirfenidone detains the histological         damage to the affected kidneys.     -   A very important observation of the study and THE FIRST OF ITS         KIND was the fact that the drug side-effects on patients with         primary nephropathy were limited to a minimum percentage of         patients and disappeared rapidly.

Application of Sustained-Release Tablets Containing Pirfenidone in the Regression of Breast Capsular Contracture

Currently, breasts play an important part in women sensitivity and constitute a femininity symbol. For this reason, in the last few years, women have found in surgery an important ally to increase the size or improve the aspect of their breasts, either for aesthetic or reconstructive purposes. In the past, several attempts were made to increase the size of breasts, using various injected or implanted materials, including elements of the body itself (1895, Czerny) such as gluteal adipose tissue. However, most of them generated complications leaving hard, painful breasts that did not have the expected shape. In 1963, Cronin and Gerow introduced the silicone implant and since that time it has been possible to obtain good results consistently (17, 18).

However, there are some risks related to this surgery. Some complications may occur after the surgery, such as infection, edema, hemorrhage, pain, slow or poor scarification, anesthetic reaction, hypoesthesia, change of the position of the implant, and most frequently, capsular contracture. This causes firmness, pain and, in severe cases, some external deformation can be seen (19, 20).

The causes and pathogenesis of capsular contracture are not clearly understood. Several publications mention a variable incidence of capsules from 0% to 74% (1), depending on the type of implant, the surface (textured or smooth), and the implantation or anatomic site (subglandular or subpectoral) (2). The causes of these capsules could be the accumulation of liquid in the breast implant bag tissues, intense inflammatory response, subclinical infection, the age of the patient, materials and the alteration of cells and molecular mechanisms in the implantation zone.

When an implant is placed, the organism reacts encapsulating the foreign body from a rejection (3-6). This immune response is mediated by cytokines and growth factors such as interleukin-1 (IL-i), IL-6, tumor necrosis factor-α (TNF-α), platelets from the derived growth factor, and transforming growth factor-β1 (TGF-β1) (7, 8). The presence of myofibroblasts in the contractured capsule has been reported always together with the production of α-smooth muscle-actin (α-SMA); the most deformed capsules showing a larger production of α-SMA, suggesting a direct function of myofibroblasts activity in the development of the contracture (8). It has also been evidenced that the number of myofibroblasts present in the tissue is proportional to the thickness of the Contractured Capsule (9). The above data were obtained with human beings.

On the other hand, various studies have used animal models of mammary capsular contracture post-placement of mammary implants. Animals such as pigs, rabbits, rats, mice have been used with variable results. Some animal models imply the addition of an implant inducing agent in order to accelerate the development of the contracture. All of them show fibrosis development, fibroblast activation, inflammation and thickness of mammary capsule (21-27).

In prior studies using rabbits and mice models, the pre-instillation of the implant bag with sodium 2-mercaptoethane sulphonate (mesna) and mitomycin C reduced the thickness of the capsule, lowered the number of fibroblasts and reduced collagen deposit (21, 22). However, said drugs are not commonly used currently in clinical practice. In order to reduce fibroblast activation and wound retraction, the infiltration of steroids on the wound and inside the implant has reported few complications. Steroids are not frequently used currently and are not recommended by implant manufacturers. Complications include skin thinning, tissue atrophy, striations, blue-colored skin, and implant exposition (28-36).

Direct Background

Pirfenidone (5 methyl-1-phenyl-2-[1H] pyridone) (PFD), a new antifibrotic agent, has shown to be efficacious both in vitro as well as in vivo, preventing and eliminating fibrous tissue in experimental models of pulmonary fibrosis (10), peritoneal adherences (11), experimental and human hepatic cirrhosis (12, 13), uterine fibromas (14), renal fibrosis (15), and scars (16). Moreover, PFD can inhibit fibroblast growth factor and TGf-31 produced by human fibroblasts.

On the other hand, it has been evidenced that Pirfenidone administered orally in female rats with silicone implants in mammary gland prevents the development of the characteristic fibrosis in the mammary capsule that finally causes the painful contracture (Matias Gancedo, Aesthetic Plastic Surgery 2008).

Because mammary implants induce fibrosis and inflammation and PFD has shown anti-fibrotic and anti-inflammatory properties in different pathologies and organs, one of the main objects of this invention is to determine the pharmacological properties of oral Pirfenidone in the post-surgery evolution of patients after the placement of mammary implants. The study was focused on the reduction of the thickness of the Periprosthetic Capsule and/or prevention of its thickening and on the prevention of the recurrence of capsular contracture.

The use of breast implants is related to complications such as Capsular Contracture (CC). This is defined as the thickening of the capsule surrounding the implant and is classified from Grade I to grade IV (Baker Scale) according to texture, implant visibility and deformity and shows an incidence ranging from 15 to 45%. Table 1. Baker Scale.

TABLE 1 Baker Scale. TABLE 1. BAKER SCALE IMPLANT IMPLANT FIRMNESS PALPATION VISIBILITY GRADE I Slight Not palpable Not visible GRADE II Minimum palpable Not visible GRADE III Moderate Easily palpable Distortion GRADE IV Severe Hard, painful and Severe distortion cold

Prior studies, both in human as well as in animal models have been used for evidencing new therapeutic embodiments for Breast Capsular Contracture. Unfortunately, most of these therapies do not generate a significant response and show a high relapse rate.

For medical research and drug development, the use of single nucleotide polymorphisms (SNPs) has been very useful. They do not vary much from one generation to the other and can be evidenced through genetic markers. A genetic marker is a DNA segment with a physical location identifiable on a chromosome.

It has been determined that Capsular Contracture appears partly as an immune response mediated by cytokines and growth factors such as Transforming Growth Factor-B1 (TGF-β1).

Rationale

The object of this study is to offer another therapeutic focus to breast capsular contracture in order to implement a treatment that reduces or eliminates the use of drugs or surgical procedures (capsulotomy, capsulectomy) described up to now for its management, obtaining a lower relapse rate and improving thus the patient's quality of life.

Study Design

It is a pilot, open, prospective, longitudinal and analytical essay in which 17 patients diagnosed with an important breast capsular contracture (Grade III and Grade IV, Baker Scale) were treated with Pirfenidone 600 mg administered orally as sustained-release tablets three times per day (every 8 hours) during six months.

A blood sample was taken from each patient in order to determine the genetic markers (TGF-31). Using PCR-RFLP, three Breast echosonographies were made, one at the beginning, the other at the end of the treatment (6 months) and the last one 6 months after the suspension of Pirfenidone treatment (12 months). Two parameters were evaluated: antero-posterior diameter and capsular thickness in all its quadrants (contrasting thickness measurements with the radiological parameters established by Tomcs Stavros, 2006 and the radiological clinical correlation of thickness vs Baker Scale established by Alon Zahavi MD, 2006 for the diagnosis of Capsular Contracture). Free liquid in the capsule was looked for, as well as retraction or rupture signs through 5-12 MHz linear or curve transductors.

During 12 months, a Breast Clinical Evaluation was also conducted on a monthly basis using Baker Classification.

Deformation, texture through palpation and sensitivity were evaluated. A registration of each evaluation was made with digital photographs. The clinical and radiological changes of each breast were evaluated by a plastic surgeon and a qualified radiologist.

The statistical analysis included 20 cases, taking into account that 3 patients presented bilateral capsular contracture of different grade in each breast; a total of 20 breasts were analyzed.

The protocol was approved by the regulatory authorities and the Ethic Committee of the Instituto Jalisciense de Cirugia Reconstructiva “Dr. Jose Guerrero Santos”, registration number 01/09. All the patients signed an informed consent at the beginning of the protocol. Besides, this study was conducted according to the Helsinki Declaration and according to the local legislation and regulations applicable to the use of a new therapeutic agent in Mexico.

Experimental Evidence/Results

All the cases included in the study showed a reduction of breast capsular contracture grade. In 70% of the cases (n=14), it concluded Without Clinical or Sonographic Evidence of Capsular Contracture (WCSECC). Among these cases, 9 (45%) were grade III and 5 cases (25%) were grade IV. The remaining 30% corresponded to grade IV cases that only reduced capsular contracture; 1 case (5%) from grade IV to grade II and 5 cases (25%) from grade IV to grade III.

Importantly, the 6-month follow up after Pirfenidone discontinuation showed that ONLY 1 case (5%) grade IV showed relapse of capsular contracture from WCSECC to grade III at the end of the study because of the use of steroids and excessive exercise.

It has to be emphasized that all the patients presenting grade III (9 cases [45%]) responded to the pirfenidone treatment ending the study Without Clinical or Sonographic Evidence of Capsular Contracture (WCSECC) (p<0.001, according to the Wilcoxon matched-pairs signed-ranks); (Table 2).

TABLE 2 Capsular contracture grade relationship according to Baker Scale; at the beginning, at 6 months and at the end of the study with Pirfenidone Contracture Grade WCSECC** I II III IV Cases Initial — — — 9 11 20  6 Months 10 5 — 5 — 20 12 months 14 — 1 5 — 20 *p < 0.001 Wilcoxon matched-pairs signed-ranks and chi² **WCSECC Without Clinical or Sonographic Evidence of Capsular Contracture. According to Alon Zahavi, MD and Stavros, MD.

The echographic findings corresponded to breast capsular contracture diagnosis, reporting an increase in the antero-posterior diameter of the capsule thickness, presence of intracapsular liquid and retraction data before the start of the Pirfenidone treatment.

A gradual reduction of the antero-posterior diameter (APD) and capsule thickness was obtained in 19 cases (95%) as evidenced through the echographies conducted at 6 and 12 months. A Student's t analysis was applied for paired samples; upon analyzing the APD a P value 5.001 was obtained contrasting the beginning and 6-month values; and a P=N. S. was obtained contrasting the 6-month and 12-month values (Table 3). In the capsule thickness comparison between quadrants, P was significant in each case as shown in Table 4. It has to be emphasized that the only case of contracture relapse (5%) showed an increase of said parameters in the sixth- to twelfth-month period.

Two cases (10%) in the patient group that passed from grade IV to grade III showed retraction data and light subcapsular liquid at the end of the study.

TABLE 3 Comparison of the Antero Posterior diameter (APD) of the breast implant, echographically measured at the beginning, at 6 months and at 12 months. Initial AP AP Diameter* at AP Diameter* at Diameter* 6 months 12 months □x 7.57 6.425 6.085 σ 2.159 2.319 2.062 T P ≤ .001 P = N. S. *Values expressed in centimeters. T for related samples; □x (Mean) and σ (Standard Deviation).

TABLE 4 Comparison of the capsule thickness at the beginning and at the end of the study per quadrant.** Implant Implant Implant Implant fibrous fibrous fibrous fibrous capsule OUQ capsule IUQ capsule OLQ capsule ILQ Beginning End Beginning End Beginning End Beginning End □X 1.505 1.18 1.6 1.19 1.775 1.185 1.86 1.115 σ 0.464 0.472 0.681 0.518 1.062 0.474 1.280 0.446 T P = .001 P = .001 P ≤ .005 P ≤ .01 *Values expressed in centimeters. **OUQ (Outer Upper Quadrant), IUQ (Inner Upper Quadrant), OLQ (Outer Lower Ouadrant), ILQ (Inner Lower Quadrant) + capsular Contracture = Capsule Thickness ≥ 1.5 mm according to Stavros, and 1.42 mm according to Alon Zahavi. T for related samples; □x (Mean) and σ (Standard Deviation).

The SNP genetic analysis for TGF-β1 (Table 5) showed that 15 of the patients (88.2%) were homozygous G/G for the genotype (codon 25; 25/Arg25 genotype Arg) and 2 patients (11.8%) were heterozygous G/C TGF-β1 for the genotype (codon 25; 25/Arg25 genotype Arg). From this it was determined that the patients with G/G genotype have a higher probability of developing breast capsular contracture.

TABLE 5 Table 5. Genotypic frequencies and allelic distribution of polymorphism TGF-β1 Arg25Pro in patients in the Breast Capsular Contracture Group and in the Control Group with breast implant. TGF-β1 (Arg25Pro) Control Patients with breast Capsular Group Contracture (n = 30) (n = 30) Group Group Control treated with treated with group with PFD capsulectomy breast (n = 17) (n = 13) implant Frequency Frequency Frequency (%) (%) (%) p¹ Genotype G/G 15 (88) 13 (100) 5 (17) 0.0001 G/C 2 (12) 0 (0) 25 (83) C/C 0 (0) 0 (0) 0 (0) Allele G 32 (94) 26 (100) 35 (58) C 2 (6) 0 (0) 25 (42)

Side effects such as stomach aches, fatigue, skin dermatosis and photosensitivity were only present in 6 patients (35%), with a mean of 10.8 days.

Finally, the statistical analysis of the ordinal scale variables was conducted with means and ranges; and for the contrasts, Wilcoxon matched-pairs signed-ranks and Chi² were used. With regard to the Ratio Interval variables, the mean and standard deviation were used; and for the contrast, Student's t test for paired samples was used in which a case is compared against another case. Table 6 summarizes integrally said comparative analysis.

TABLE 6 Table 6. Comparison of Breast Capsular Contracture at the beginning and at 12-month follow up in both groups. BAKER SCALE Beginning of 12-month the study follow-up GROUP Mean (Range) Mean (Range) P** PFD (n = 20) 4 (3-4) 0.5 (0-3) 0.0001 CAPSULECTOMY 4 (3-4) 2 (1-3) 0.001 (n = 14) P* NS ≤0.006 Table 6. Results of the statistical analysis between the study groups. *U de Mann-Whitney. **Wilcoxon for paired samples. NS = no Significant.

Pirfenidone Anti-TNF-α and Anti-TGF-β1 Action in Sustained-Release Tablets

Pirfenidone, prepared according to the previously described quantitative formula for extended release and before conversion into tablets, was used for conducting the experiments described hereinafter in order to demonstrate its anti-TNF-α and anti-TGF-β1 action.

Basically, Pirfenidone efficacy at inducing fibrosis regression, both at experimental level as well as at human treatment level is supported by its inhibitory action against TNF-α and TGF-Q synthesis and production.

It is essential to highlight that it has been demonstrated both in vitro as well as in vivo that Pirfenidone selectively inhibits NF-kβ, lowering dramatically the activation of genes codifying for pro-inflammatory proteins (TNF-α and TGF-β1).

Experimental Evidence/Results

TGF-β1 serum levels determination in female rats submitted to the placement of silicone implants in mammary glands for inducing contracture development are shown in FIG. 5. The animals were administered a daily regimen of oral Pirfenidone during 21 days. In the same diagram it can be seen that also animals with chronic hepatic damage by hepatotoxic CC14 (Carbon Tetrachloride) have a lower TGF-31 serum level when treated with Pirfenidone. TGF-31 levels were determined through a commercial ELISA kit.

TNF-α serum levels determination in female rats submitted to the placement of silicone implants in mammary glands for inducing contracture development are shown in FIG. 6. The animals administered a daily regimen of oral Pirfenidone during 21 days. In the same diagram, it can be seen that also animals with chronic hepatic damage by CC14 have a lower TNF-a serum level when treated with Pirfenidone. TNF-α levels were determined through a commercial ELISA kit.

REFERENCES

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1-15. (canceled)
 16. A sustained-release tablet comprising pirfenidone and one or more excipients, for sustained release of pirfenidone over 12 hours.
 17. The tablet of claim 16, wherein the tablet comprises approximately 100 mg to approximately 850 mg of pirfenidone.
 18. The tablet of claim 16, wherein the tablet comprises approximately 600 mg of pirfenidone.
 19. The tablet of claim 16, wherein at least one excipient is microcrystalline cellulose.
 20. The tablet of claim 16, wherein at least one excipient is hydroxypropylmethylcellulose (HPMC).
 21. The tablet of claim 20, wherein the HPMC is low viscosity HPMC.
 22. The tablet of claim 20, wherein the HPMC is high viscosity HPMC.
 23. The tablet of claim 16, wherein at least one excipient is silicon dioxide.
 24. The tablet of claim 16, wherein at least one excipient is sodium stearyl fumarate.
 25. The tablet of claim 16, wherein the tablet comprises the excipients of microcrystalline cellulose, low viscosity HPMC, and high viscosity HPMC.
 26. The tablet of claim 16, wherein the tablet comprises microcrystalline cellulose, low viscosity HPMC, high viscosity HPMC, silicon dioxide, and sodium stearyl fumarate.
 27. The tablet of claim 16, for oral administration.
 28. The tablet of claim 16, for use in treating pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, or breast capsular contracture, or for use in inhibiting the progression of chronic renal failure.
 29. A method of treating renal fibrosis, hepatic fibrosis, liver cirrhosis, or breast capsular contracture, or inhibiting the progression of chronic renal failure comprising administering one or more sustained-release tablets of claim
 16. 30. The method of claim 29, wherein a daily dosage comprises approximately 400 mg to approximately 2400 mg of pirfenidone per day.
 31. The method of claim 29, wherein the one or more tablets are administered orally 1 to 4 times per day.
 32. The method of claim 29, wherein the one or more tablets is administered for 21 days.
 33. The method of claim 29, wherein decreased toxic effects are observed in a treated subject.
 34. A process for preparing the sustained-release tablet of claim 16, wherein the process comprises the following steps: (a) screening the pirfenidone and silicon dioxide; (b) mixing the pirfenidone and the silicon dioxide; (c) screening microcrystalline cellulose, low viscosity hydroxypropylmethylcellulose (HPMC), and high viscosity hydroxypropylmethylcellulose (HPMC); (d) mixing the screened microcrystalline cellulose, low viscosity HPMC, and high viscosity HPMC with the mixture produced in step (b); (e) screening sodium stearyl fumarate; (f) mixing the screened sodium stearyl fumarate with the mixture in step (d); and (e) forming the tablet from the mixture produced in step (f).
 35. The process of claim 34, wherein the tablet comprises the following compression parameters: average weight: 850 mg±5%; hardness: maximum 10 kgF; and brittleness: lower than 1%. 